Human hnRNP genes have been reported to be involved in human malignancies and several hnRNPs are promising biomarkers of lung, head and neck, colon, breast, and pancreatic cancers. The present study investigated the clinicopathologic and biological significance of hnRNP E2 gene expression in oral cancer. Human hnRNP E2 was significantly downregulated in oral cancer tissues compared to normal one (P < 0.0001) as determined by quantitative real‐time reverse transcription PCR. The expression of hnRNP E2 is correlated with histology, being lower in moderate and poorly differentiated squamous cell carcinoma (SCC) compared to well‐differentiated SCC. Transient transfection of hnRNP E2 in cancerous cell lines resulted in reduced cell viability and increased apoptotic nuclei. Compared to control transfectants, cells with higher expression showed an increase in the number of apoptotic cells by annexin‐PI staining and an increase in caspase activity. The present study thus implicates downregulation of hnRNP E2 as a novel mechanism to enhance the resistance of cancer cells to apoptosis. © 2006 Wiley‐Liss, Inc.